The Link Between Adenovirus And Cancer

Adenovirus – an overview

Adenoviruses are double-stranded DNA members of the Adenoviridae family. The name “Adenovirus” is derived from their initial isolation source – the human adenoid gland in 1953.¹ These viruses affect a wide range of hosts, including humans, causing various illnesses, including respiratory, gastrointestinal, and eye infections.

Adenoviruses are at higher risk of infecting children and immunocompromised individuals and are mostly transmitted via inhalation of aerosolized droplets, or faeco-oral spread via drinking water, swimming pools, etc.² In nature, they are mostly waterborne, common sources including water bodies contaminated with sewage and human faeces.

What are oncoviruses?

An oncovirus, oncogenic virus or tumour/cancer virus is an entity that promotes uncontrolled cell growth and transformation, resulting in malignant tumours. Oncoviruses are mostly DNA viruses such as human papillomavirus (HPV) (major cause of cervical cancer), hepatitis B virus (associated with hepatocarcinoma), Epstein-Barr virus, adenovirus, human cytomegalovirus; and some RNA viruses such as certain retroviruses, RNA viruses associated with hepatitis C, etc. Oncoviruses are responsible for about 12% of total cancer occurrence.³

Oncogenic viruses are theorised to have two main mechanisms of action – a direct mechanism which involves the addition of oncogenic viral genes into the host cell. This acts directly or enhances already present proto-oncogenes present in the cell, resulting in uncontrolled cell growth.⁴ The indirect mechanism involves chronic inflammation, resulting in malignancy.

Direct oncogenic mechanisms introduce foreign viral antigens into cells, thus making detection easier. This behaviour also makes them more dangerous for immunocompromised (for example, AIDS patients) and immunosuppressed (for example, transplant) patients.

How do adenoviruses cause infection?

Ordinarily, adenoviruses are common pathogens of animals and can cause respiratory, conjunctival, and occasionally gastrointestinal conditions (carcinogenic potential discussed in next section).

The primary site of action for human adenoviruses is the respiratory tract. Adenovirus is transmitted through respiratory secretions, following that, they will locally multiply at their portals of entry. After successful implantation at the local site, the virus spreads extracellularly (mostly) and intracellularly to adjacent areas, and may also occur via diffusion through fluid surfaces such as the mucous layer of the respiratory tract. This leads to localised disease and immune response.⁵

Can adenoviruses cause cancer?

The theoretical basis of oncogenicity

The rationale of oncogenicity is based on the presence of genes in human adenoviruses known to be contributors to the cellular pathway leading to malignancy. These include the E1A, E1B, and E4 genes.⁶ Another requirement is the occurrence of abortive infections, which develop when a virus penetrates a host cell but does not complete its replication cycle – the infection is “abortive”, and does not produce any new viral particles. During some of these abortive infections, a part of the adenoviral DNA may be integrated into the host DNA, which thus follows the previously mentioned direct mechanism of oncogenic malignancy.⁷

What current research tells us

Human adenoviruses were among the first human viruses to be able to cause cancer in non-human models – human type 12 adenoviruses elicited the growth of malignant intrapulmonary tumours in hamsters within 3 months.⁸ However, as of writing this article, there are no known cases of human adenoviruses causing cancers in humans.⁶

Studies have reported that human adenoviruses are unable to evade natural killer cells and T-cell driven immune responses of the host, which are responsible for destroying virally transformed cells. This reasoning is further validated by the observation of oncogenic transformation in rodent cell cultures which lack T-cell mediated immunity.^9,10

In theory, adenoviruses may pose an oncogenic risk to immunosuppressed and immunocompromised humans, however, this has not been scientifically proven due to the ethical challenges of conducting human trials with potentially oncogenic entities.

The role of adenoviruses in treatment – oncolytic viral therapy

Oncolytic viral therapy is a modern treatment modality for fighting cancers with the help of viruses which are used to selectively target and attack tumour cells. The viruses, known as oncolytic viruses can be bioengineered to reduce their ability to attack normal cells and specifically target tumour cells, and additionally, these viruses can also trigger an immune response in the host, thus potentially signposting and destroying malignant cells.¹¹

Adenoviruses have shown the potential to be engineered to act as vectors which may alter the tumour microenvironment. They may act via two mechanisms of action – first, adenoviruses may deliver transgenes to the cell that code for tumour suppressor gene (p53), the expression of which arrests the cell cycle and stops uncontrolled cell division. Alternatively, they may be deployed as oncolytic adenoviruses which directly terminate the tumour cells.¹²

Adenoviral vectors

Adenoviruses which have been bioengineered to improve their safety for use in humans, and gene therapy effectiveness are known as adenoviral vectors. Based on their development, three generations of adenoviral vectors have been identified:¹²

• First-generation adenoviral vectors: These vectors have the E1 and E3 genes deleted to prevent virus replication in the host (improves safety). However, they are still prone to triggering an immune response
• Second-generation adenoviral vectors: In addition to E1 and E3, E2 and E4 genes are deleted as well thus increasing their capacity to carry therapeutic genes. They still pose a threat, but it is reduced compared to the previous generation
• Third-generation adenoviral vectors: These are also known as high-capacity adenoviral vectors (HCAds) as almost all viral genes are deleted in these vectors. For their replication, they are dependent on an additional adenoviral “helper virus”. Thus, they are also called “helper dependent or gutless adenoviral vectors”

Summary

From a natural virus being accidentally discovered shrinking a tumour to the use of engineered oncolytic viruses to target cancer cells, the use of oncolytic viral therapy has shown much promise in recent times.¹³ Adenovirus, instead of being a risk of cancer, serves as an important potential genetic vector in the war against cancer.

Currently, the sheer variation in tumour composition and molecular structure (tumour heterogeneity) is the primary obstacle to the development of oncolytic viral therapies. However, with ongoing clinical trials on adenoviral oncolytic therapy and other treatment combinations (viral + conventional radiotherapy, for example), adenoviruses likely play a significant role in the future of cancer treatment.^14,15